The four projects described will address the global hypothesis that TNF- alpha is a proximal mediator of the overall inflammatory response to burn trauma; we further propose that TNF-alpha modulates burn related down stream organ injury via mechanisms that are highly specific for each organ. Finally, we hypothesize that genetic polymorphisms for TNF modulate the overall cytokine response to trauma. The first project will examine the signaling mechanisms regulating local synthesis of TNF and define the mechanisms by which local TNF synthesis alters organ function. The second project will examine the contribution of locally derived TNF to posture apoptosis of the cardiomyocyte and endothelial cells (both pulmonary and coronary); we propose that apoptosis increases endothelial permeability and mediates the posture "capillary leak". The third Project will examine whether TNF potentiation of neutrophil- endothelial adherence alters the actin microfilaments of the endothelial cell cytoskeleton, rendered these cells susceptible to hydrostatic injury and contribution to posture changes in pulmonary microvascular permeability. The fourth project will determine whether the presence of gene-polymorphisms identifies "high-risk" patients after burn trauma with regard to a net pro-inflammatory response that culminates in pulmonary and cardiac dysfunction. These projects (using an identical animal model) are based rich collaborative efforts which have produced significant preliminary data, and the interrelationship of these projects has allowed us to address several aspects of single organ function as well as whole body response to burn trauma. with regard to a new pro-inflammatory response that culminates in pulmonary and cardiac dysfunction. These projects (using an identical animal model) are based rich collaborative efforts which have produced significant preliminary data, and the interrelationship of these projects has allowed us to address several aspects of single organ function as well as whole body response to burn trauma. The availability of transgenic approaches couples with well controlled pharmacologic studies should define specific signal transduction mechanisms by which turn trauma promotes organ injury and dysfunction. Through the first 34 years of this center grant, we have seen that basic science studies have guided the development of fluid resuscitation, pharmacologic approaches to treat trauma and the development of new techniques for wound coverage, skin grafting and topic antibiotic therapies. Thus the overall goal of these cumulative projects is to design better therapeutic strategies to improve outcome in the patient with major burn injury.